Most of threo-3-amino-2-hydroxybutanoylaminoacetic acids prepared according to this invention are known from U.S. Pat. Nos. 4,029,547 and 4,052,449, British Patent Nos. 1,510,477 and 1,540,019.
For example, (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoylaminoacetic acid (herein after referred to simply as bestatin) is a least toxic substance isolated from culture filtrates of Streptomyces olivoreticuli as an aminopeptidase B inhibitor (referred to U.S. Pat. No. 4,029,547) by H. Umezawa, et al., which has been found to exhibit an increasing effect to immunoresponse such as delayed hypersthesia, activate in vivo defense mechanism and has inhibitive effects for cancer (referred to Japanese Patent Laid-Open Publication No. 117435/1977) and the compound is expected to be useful as a pharmaceutical.
It is also known that several 3-amino-2-hydroxybutanoylaminoacetic acids other than bestatin have equal or more inhibitory activity to aminopeptidase B than bestatin and a synthetic process therefor is disclosed in British Patent No. 1,510,477. In the process described in the British Patent, however, while (2S,3R)-3-amino-2-hydroxybutanoic acid, for example, as an intermediate for bestatin is synthesized through the steps shown below, the process has various defects as detailed later. ##STR9##
(R)-phenylalanine (1) is converted to a benzyloxycarbonyl derivative (2), which is then condensed with 3,5-dimethylpyrazole by using dicyclohexylcarbodiimide. The 3,5-dimethylpyrazolide (3) is reduced to benzyloxycarbonyl-(R)-phenylalaninal (4) with lithium aluminum hydride, which is then changed to the corresponding adduct (5) by reaction with sodium hydrogen sulfite and further to the cyanohydrin (6) through reaction with a cyanide. The above derivative is hydrolyzed under an acidic condition into (2RS,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid (7), which is again allowed to react with a benzyloxycarbonylating reagent to convert to (2RS,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-butanoic acid (8). The acid is fractionally crystallized into (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (9) by using brucine.
Although the above process can be conducted with no troubles in a laboratory scale, it is not suited to large scale production so that the process includes the use of much expensive (R)-phenylalanine which is not a natural amino acid, the use of highly ignitable lithium aluminum hydride for the reduction of the pyrazolide, as well as the use of a very poisonous cyanide in synthesis of cyanohydrin.
In view of the above, the inventors have made an earnest study seeking for a process suited to mass production with no foregoing defects and, accomplished this invention.
The process according to this invention can produce the end products at a high yield without using an expensive amino acid such as (R)-phenylalanine and with no use of a cyanide, and thus it is much suited to the mass production.